Genetics Update

Mar

23

The New York Times, March 22, 2011, by Jane E. Brody — Antibiotics are important drugs, perhaps the most important. In a world beset with “an unprecedented wave of new and old infections,” as one expert recently wrote, it is critically important that antibiotics work well when people need them.

But antibiotics are frequently misused — overprescribed or incorrectly taken by patients, and recklessly fed to farm animals. As a result, lifesaving antibacterial drugs lose effectiveness faster than new ones are developed to replace them.

Each year, 100,000 people in the United States die from hospital-acquired infections that are resistant to antibiotics, according to the Infectious Diseases Society of America.

These concerns led Dr. Zelalem Temesgen, an infectious disease specialist at the Mayo Clinic in Rochester, Minn., to create a 15-part “Symposium on Antimicrobial Therapy,” published in February in The Mayo Clinic Proceedings. The series is intended in part to help practicing physicians know when and how antibiotics should be used — and, equally important, when they should not.

Improving how antibiotics are prescribed can do more than curb resistance. It can save lives and money by reducing adverse drug reactions and eliminating or shortening hospital stays, Dr. Temesgen said.

The first installment in the series, based on guidelines developed by the infectious diseases society and published with Dr. Temesgen’s introduction, was devoted to helping doctors practice better medicine. It also can help patients better understand how and when antibiotics work best, and it can arm them with the right questions when an antibiotic prescription is being considered.

Patient-Tailored Therapy

The report, prepared by three infectious disease specialists — Surbhi Leekha, now at the University of Maryland, and Drs. Christine L. Terrell and Randall S. Edson, both at the Mayo Clinic — urged doctors to avoid a “one size fits all” approach to antibiotics. Rather, they said, many individual factors must be taken into account to ensure the right drug and the right dose are prescribed for each patient.

It is often up to the patient to make sure the prescribing physician is aware of these influential factors. They include:

Kidney and liver function. The kidneys and liver eliminate drugs from the body. If the organs are not working well, toxic levels can accumulate in the bloodstream.

Age. Considering a new antibiotic? This is no time lie about your age. “Patients at both extremes of age handle drugs differently, primarily due to differences in body size and kidney function,” the experts wrote. A face-lift and hair coloring may disguise your geriatric status, but they will not help your kidneys process drugs as well as they did in your youth. In some cases, in young, otherwise healthy patients, higher drug doses may be needed to be sure that therapeutic levels are maintained.

Pregnancy and nursing. Some antibiotics given to a pregnant or lactating woman can adversely affect her baby, and it is critically important to tell the prescribing doctor if you are pregnant (or might be pregnant) or nursing. The risk of drug-induced birth defects is highest in the first three months of pregnancy; during the last three months, drugs are eliminated from the body more quickly, and higher doses may be needed to maintain a therapeutic blood level.

Drug allergy or intolerance. Make sure the doctor knows if you have ever had a bad reaction to an antibiotic. But — and this is important — neither you nor your doctor should assume you are allergic to, for example, penicillin because you once developed a rash while taking it. The rash could have been caused by the illness or something else entirely.

When an allergy is suspected, a skin test should be performed to confirm it so that the ideal antibiotic treatment is not mistakenly ruled out in the future.

“It has been shown that only 10 percent to 20 percent of patients reporting a history of penicillin allergy were truly allergic when assessed by skin testing,” the experts wrote.

In an interview, Dr. Edson said it is possible to rapidly desensitize a patient to a needed antibiotic by administering progressively larger oral doses of the drug.

Recent antibiotic use. Tell the doctor if you recently took an antibiotic. If you develop a bacterial illness within three months of antibiotic therapy, you may have a drug-resistant infection that requires use of an alternate class of medication.

Genetic characteristics. Some people are born with factors that make them especially vulnerable to bad reactions from certain antibiotics. For example, in those with a condition known as G6PD deficiency, which is most common among blacks, certain antibiotics can lead to the destruction of red blood cells. Patients who could be at risk should be tested for G6PD deficiency beforehand.

The Value of a Culture

When patients arrive at the doctor’s office with an inflamed throat, deep cough, high fever or unrelenting sinus pain, more often than not they are given prescriptions for antibiotics. The experts noted that it is sometimes reasonable to treat an infection without first getting a culture of the responsible organism — like when the patient’s symptoms are typical of a known bacterial infection.

“Doctors do have to exercise clinical judgment in many cases,” Dr. Edson said. For example, he and his co-authors wrote, “Cellulitis is most frequently assumed to be caused by streptococci or staphylococci, and antibacterial treatment can be administered in the absence of a positive culture.”

Likewise, they added, community-acquired pneumonia (that is, pneumonia that develops somewhere other than a hospital) can be treated with an antibiotic without patients first receiving a diagnostic test.

But all too often, the cause of a patient’s symptoms is not bacterial and may not even be an infection. In these cases, taking an antibiotic will do no good and may even be harmful. Possible nonbacterial causes include a viral infection (which will not respond to an antibiotic), a connective tissue disorder or an allergy, Dr. Edson said.

He and his co-authors emphasized the importance of getting a laboratory to identify the responsible organism when the likely cause of symptoms is not apparent or when patients have a serious or life-threatening infection, require long-term antibiotic therapy or fail to benefit from the drug chosen initially.

Sometimes a culture will indicate the need to administer two antibiotics simultaneously — for example, when the infectious organism produces an enzyme that inactivates what would otherwise be the most effective antibacterial drug.

The experts also urged that if patients were first treated with a broad-spectrum antibiotic (one that attacks a number of different bacteria), doctors should consider switching to a narrow-spectrum drug that targets the specific cause once it is identified through a laboratory culture. This could reduce the risk of other bacteria becoming resistant to the broad-spectrum drug.

Mar

23

Genetics Society of America, March 22, 2011 — A team of scientists from the University of Oxford, U.K. have taken lessons from Adam Smith and Charles Darwin to devise a new strategy that could one day slow, possibly even prevent, the spread of drug-resistant bacteria. In a new research report published in the March 2011 issue of Genetics, the scientists show that bacterial gene mutations that lead to drug resistance come at a biological cost not borne by nonresistant strains. They speculate that by altering the bacterial environment in such a way to make these costs too great to bear, drug-resistant strains would eventually be unable to compete with their nonresistant neighbors and die off.

“Bacteria have evolved resistance to every major class of antibiotics, and new antibiotics are being developed very slowly; prolonging the effectiveness of existing drugs is therefore crucial for our ability to treat infections,” said Alex Hall, Ph.D., a researcher involved in the work from the Department of Zoology at the University of Oxford. “Our study shows that concepts and tools from evolutionary biology and genetics can give us a boost in this area by identifying novel ways to control the spread of resistance.”

The research team measured the growth rates of resistant and susceptible Pseudomonas aeruginosa bacteria in a wide range of laboratory conditions. They found that the cost of antibiotic resistance has a cost to bacteria, and can be eliminated by adding chemical inhibitors of the enzyme responsible for resistance to the drug. Leveling the playing field increased the ability of resistant bacteria to compete effectively against sensitive strains in the absence of antibiotics. Given that the cost of drug resistance plays an important role in preventing the spread of resistant bacteria, manipulating the cost of resistance may make it possible to prevent resistant bacteria from persisting after the conclusion of antibiotic treatment. For instance, new additives or treatments could render antibiotic resistance more costly for bacteria, making it less likely that the resistant strains will persist at the end of treatment.

“If we’ve learned one thing about microscopic organisms over the past century, it’s that they evolve quickly, and that we can’t stop the process,” said Mark Johnston, Editor-in-Chief of the journal GENETICS. “This research turns this fact against the bacteria. This is an entirely new strategy for extending the useful life of antibiotics, and possibly for improving the potency of old ones.”

Antibiotic Resistance Is Not Just Genetic

Wild-type Pseudomonas aeruginosa bacterium. (Credit: Pierre Cornelis)

Society for General Microbiology — Genetic resistance to antibiotics is not the only trick bacteria use to resist eradication- they also have a second defence strategy known as persistence that can kick in.

Researchers reporting in the Journal of Medical Microbiology have now demonstrated for the first time that interplay occurs between the two mechanisms to aid bacterial survival. The findings could lead to novel, effective approaches to treat multi-drug resistant (MDR) infections.

‘Persister’ bacterial cells are temporarily hyper-resistant to all antibiotics at once. They are able to survive (normally) lethal levels of antibiotics without being genetically resistant to the drug. These cells are a significant cause of treatment failure yet the mechanism behind the persistence phenomenon is still unclear.

Scientists from Centre of Microbial and Plant Genetics, at the Katholieke Universiteit Leuven, Belgium found that the number of persister cells isolated from Pseudomonas aeruginosa infections decreases when the bacterial population shows genetic resistance to the antibiotic fosfomycin.

P. aeruginosa is an opportunistic human pathogen and a significant cause of hospital-acquired infections. It can cause fatal infections in people suffering from cystic fibrosis. The bacterium is notorious for its ability to develop resistance against commonly-used antibiotics and treatment failure is common.

Professor Jan Michiels who led the study explained that persister cells are a major contributor to treatment failure. “Persister cells are produced in low numbers, but nevertheless make it almost impossible to completely remove the bug from the patient. As a result, eradication of infections through antibiotic treatment usually takes a long time,” he said. “Our work shows that antibiotic treatment may also influence the number of persisters formed.”

Co-administration therapies are being developed to treat MDR infections, in which drugs targeting non-essential cellular functions are combined with antibiotics. Professor Michiels explained that targeting persistence is an attractive option. “Ideally both susceptible and persistent cells would be targeted in a single therapy, but firstly we need to understand more about the interplay between genetic resistance and persistence to avoid stimulating one or the other. Unravelling the mechanism behind bacterial persistence is really important to enable us to optimise treatments of chronic bacterial infections.”

Mar

23

Society for General Microbiology — Short courses of antibiotics can leave normal gut bacteria harboring antibiotic resistance genes for up to two years after treatment, say scientists writing in Microbiology.

The researchers believe that this reservoir increases the chances of resistance genes being surrendered to pathogenic bacteria, aiding their survival and suggesting that the long-term effects of antibiotic therapy are more significant than previously thought.

Antibiotics that are prescribed to treat pathogenic bacteria also have an impact on the normal microbial flora of the human gut. Antibiotics can alter the composition of microbial populations (potentially leading to other illnesses) and allow micro-organisms that are naturally resistant to the antibiotic to flourish.

The impact of antibiotics on the normal gut flora has previously been thought to be short-term, with any disturbances being restored several weeks after treatment. However, the review into the long-term impacts of antibiotic therapy reveals that this is not always the case. Studies have shown that high levels of resistance genes can be detected in gut microbes after just 7 days of antibiotic treatment and that these genes remain present for up to two years even if the individual has taken no further antibiotics.

The consequences of this could be potentially life-threatening explained Dr Cecilia Jernberg from the Swedish Institute for Infectious Disease Control who conducted the review. “The long-term presence of resistance genes in human gut bacteria dramatically increases the probability of them being transferred to and exploited by harmful bacteria that pass through the gut. This could reduce the success of future antibiotic treatments and potentially lead to new strains of antibiotic-resistant bacteria.”

The review highlights the necessity of using antibiotics prudently. “Antibiotic resistance is not a new problem and there is a growing battle with multi-drug resistant strains of pathogenic bacteria. The development of new antibiotics is slow and so we must use the effective drugs we have left with care,” said Dr Jernberg. “This new information about the long-term impacts of antibiotics is of great importance to allow rational antibiotic administration guidelines to be put in place,” she said.

Mar

23

Drug Resistant Super Bugs

Tel Aviv University — Antibiotics can work miracles, knocking out common infections like bronchitis and tonsillitis. But according to the Center for Disease Control, each year 90,000 people in the U.S. die of drug-resistant “superbugs” — bacteria like Staphylococcus aureus (MRSA), a deadly form of staph infection resistant to normal antibiotics. Although hospital patients are particularly susceptible as a result of open wounds and weakened immune systems, the bacteria can infect anyone.

Dr. Micha Fridman of Tel Aviv University’s Department of Chemistry is now developing the next generation of antibiotics designed to overcome this kind of bacteria. And the key, he says, is in the bacteria itself.

“We took the mechanism of bacterial resistance and used this mechanism itself to generate antibiotics,” explains Dr. Fridman. “It’s thanks to these bacteria that we can develop a better medication.” Conducted in collaboration with Prof. Sylvie Garneau-Tsodikova from the University of Michigan at Ann Arbor, Dr. Fridman’s research was highlighted recently in the journal ChemBioChem.

Fighting from within

According to Dr. Fridman, certain bacterial strains include enzymes which help the bacteria to inactivate antibiotics. When the enzymes meet with these antibiotics, they chemically alter the drug, making the antibiotic ineffective and unable to recognize its target.

Turning this powerful mechanism against the bacteria itself, the team isolated the antibiotic-inactivating enzymes from the bacteria, then integrated them into the drugs. With this alteration, the modified antibiotics proved to be effective against typically resistant bacterial strains.

At the heart of this development, says Dr. Fridman, was the chemical modification of the parent drug. Once the researchers identified how the bacteria incapacitated the antibiotics, they were able to create a drug that could block bacterial resistance while maintaining the integrity of the antibiotic.

Killing bacteria, saving lives

These new antibiotics will be a vast improvement on today’s drugs, says Dr. Fridman. When fully developed, they could be used to treat infections that are now considered difficult if not impossible to treat with current antibiotics.

Dr. Fridman says that, while the new antibiotics are a few years away from the marketplace, the ability to beat bacterial resistance will be invaluable for the future of health care.

Mar

23

When it comes to the problem of simultaneous consumption of antibiotics and alcohol, we must not forget the fact that the scope of this issue also covers thousands of other prescription drugs which do not fall in the category of antibiotics. Statistics suggest that no less than 70 percent of the adult population in the United States is consuming alcohol from time to while, while about 10 percent of adults regularly drink everyday. If those 10 percent people do not interrupt the habit of daily consumption, then surely they will end up with an instance of simultaneous consumption of antibiotics and alcohol, apart from other prescription drugs.

However, among all the demographic groups, the population segment under the greatest threat of the ill effects of the simultaneous use of antibiotics and alcohol is concerned, are the elderly, especially those above the age 65, who consume just about a third of all the prescription drugs. Since the greatest risk of the consumption of antibiotics and alcohol together is the prolonging or aggravation of the side effects of the drug being used, the older people are more likely to get affected from it than any other people.

Physicians do keep in mind such risks and strictly instruct the patients to avoid the use of alcohol. Consuming antibiotics and alcohol does not really prove lethal, but of course that depends on the kind of interaction of both the drugs that takes place in a particular case, the risk and intensity increase with the age group. Therefore, seniors should especially take care that they avoid the consumption of antibiotics and alcohol, since it could become life threatening in some cases. Better safe than sorry.

If you enjoy having an alcoholic beverage, but have been prescribed antibiotics for a particular medical condition recently, then surely you would be encountering the dilemma of whether you should use antibiotics and alcohol together or not. There certainly are some potentially dangerous and even life-threatening effects of the consumption of antibiotics and alcohol simultaneously. But there are some drugs that you should strictly take care of not to take while you consume alcohol. There are just a few groups to keep in mind in this regard, during the use of which the use of alcohol should be strictly avoided.

Among the antibiotics during which the intake of alcohol should be completely avoided are Atabrine or Antimalarial Quinacrine, Furazolidone or Furoxone, Griseofulvin or Grisactin, Tinidazole and Metronidazole. The use of alcohol with these drugs could possibly cause various side effects, such as headache, nausea and vomiting, racy heartbeat, shortness of breath, palpitations and low blood pressure.

Of course, the adverse effects of the simultaneous use of drugs with alcohol are not only confined to antibiotics, but to several other drugs as well. You should avoid using alcohol while taking anesthetics, antidepressants, anticoagulants, antihistamines and drugs taken by people suffering from cardiovascular diseases. There are a number of chemicals which could react with the body in such a way that it could give rise to complications due to the simultaneous consumption of alcohol with these drugs.

It is always the best idea to consult your physician and get a clear advice over the use and risks of antibiotics and alcohol together and you should avoid experimenting with these drugs yourself at all costs.